Dixon left Mississippi for Chicago in 1936; a year later he was the IllinoisGolden Glovesheavyweight champion in the novice category. Once Dixon even sparred with Joe Louis. Despite such early success, however, his pro career lasted only four fights. A brawl with his manager over money in the boxing commissioner's office ended whatever professional boxing dreams Dixon had.

In 1939 he began playing the bass and, along with guitarist Leonard "Baby Doo" Caston, formed the Five Breezes. The group played Chicago clubs and did a little recording until 1941 when Dixon, who had declared himself a conscientious objector, was arrested for refusing to serve in the U.S. armed forces.

After serving his sentence Dixon formed a new group, the Four Jumps of Jive, which regularly performed in Chicago clubs and recorded for Mercury in 1945. That same year Caston returned to Chicago and resumed his musical partnership with Dixon. The two formed the Big Three Trio with guitarist Bernardo Dennis. The Big Three remained active until 1952.

While playing with the Big Three Trio, Dixon was also jamming with Muddy Waters and other bluesmen in the clubs of Chicago's South Side. During one late-night jam at the Macomba Lounge, Dixon met Phil and Leonard Chess, the club's owners. The Chess brothers had recently started Chess Records, and they offered Dixon a part-time job with the label in 1948. He accepted, and after the breakup of the Big Three Trio, Dixon went to work for Chess full-time.

It wasn't until 1954, when Waters recorded Dixon's "Hoochie Coochie Man," Howlin' Wolf recorded "Evil," and Little Walter & His Jukes cut "Mellow Down Easy," that Dixon's reputation in the Chicago blues community blossomed. Dixon also began to work as a session musician; he played bass in the Chess house band, recording with Waters, Berry, Bo Diddley, Little Walter, and Jimmy Witherspoon, among others. Dixon also began arranging and producing sessions for Chess, but it was his composing talent that was most in demand. In addition to the above-mentioned originals, Dixon also wrote such blues standards as "The Seventh Son," "Wang Dang Doodle," and "You Can't Judge a Book by Its Cover," all of which were covered by a number of blues artists.

Dixon's tenure with Chess was interrupted in 1957 when he went to work for Cobra Records. During the two years that the label was in existence, Dixon worked with Magic Sam, Otis Rush, and Buddy Guy, the three guitarists who would create the West Side Sound of the Chicago blues in the late '50s and '60s. When Cobra folded, Dixon returned to Chess and stayed with the company throughout most of the 1960s. During this time he performed with the American Folk Blues Festival package in Europe and formed the Chicago Blues All-Stars, his touring and recording band.

In 1980 Dixon was inducted into the Blues Foundation's Hall of Fame. He continued playing club dates and festivals, both in the U.S. and abroad.

Dixon created the Blues Heaven Foundation in 1982 with royalty money from his song catalog. The aim of the nonprofit organization, which is still active, is to keep the blues alive through such programs as blues-in-the-schools and scholarship funds. A year later he published his autobiography, I Am the Blues (written with Don Snowden). By 1990, Dixon's ill health forced him to perform only part-time with the Chicago Blues All-Stars, though he remained active with his Blues Heaven Foundation. He died of a heart ailment in 1992.